The molecular genetics of Marfan syndrome and related disorders

Peter N Robinson ^1*, Emilio Arteaga-Solis ², Clair Baldock ³, Gwenaëlle Collod-Béroud ⁴, Patrick Booms ⁵, Anne De Paepe ⁶, Harry C Dietz ⁷, Gao Guo ⁸, Penny A Handford ⁹, Daniel P Judge ¹⁰, Cay M Kielty ³, Bart Loeys ⁷, Dianna M Milewicz ¹¹, Andreas Ney ¹², Francesco Ramirez ¹³, Dieter P Reinhardt ¹⁴, Kerstin Tiedemann ¹⁴, Pat Whiteman ⁹ and Maurice Godfrey ¹⁵

¹ Institute of Medical Genetics, Charité University Hospital, Germany
² Mount Sinai School of Medicine New York University, United States
³ University of Manchester, United Kingdom
⁴ Institut Universitaire de Recherche Clinique Montpellier, France
⁵ University of Leeds, United Kingdom
⁶ Centre for Medical Genetics Ghent University Hospital, Belgium
⁷ Howard Hughes Medical Institute, United States
⁸ Institute of Medical Genetics, Charit&eacu University Hospital, Humboldt University, United States
⁹ University of Oxford, United Kingdom
¹⁰ Johns Hopkins University School of Medicine, United States
¹¹ University of Texas Medical School at Houston, United States
¹² Institute of Medical Genetics, Charité University Hospital, Humboldt University, Berlin, Germany
¹³ Research Division of the Hospital for Special Surgery, United States
¹⁴ McGill University, Canada
¹⁵ University of Nebraska Medical Center, United States

^* To whom correspondence should be addressed. E-mail: peter.robinson{at}charite.de.

Accepted 9 March 2006

Abstract

Marfan syndrome, a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The leading cause of premature death in untreated persons with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of Marfan syndrome and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signaling as well as other changes in matrix-cell interactions. The purpose of this review is to provide a comprehensive overview of recent advances in the molecular biology of fibrillin and fibrillin-rich microfibrils. Mutations in FBN1 and other genes found in Marfan syndrome and related disorders will be discussed, and novel conceptions concerning the complex and multiple mechanisms of pathogenesis of Marfan syndrome will be explained.

Keywords: Marfan syndrome, TGFbeta, fibrillin

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